WO2003031455A1 - Optically active dihydroxycyclohexane compounds and process for producing optically active hydroxyethylenedihydroxycycohexane compound - Google Patents

Abstract

Optically active dihydroxycyclohexane compounds represented by the following general formulae (1) and (2) or the enantiomers of these. (In the formulae, R represents halogeno, substituted silyl, or a substituted boron or substituted tin group; R' and R' each independently represents substituted alkyl, halogeno, substituted silyl, or a substituted boron or substituted tin group; and X and Y each represents hydrogen, a hydroxy-protecting group, or a solid phase having the protecting group at an end.)

Description

 Specification

Method for producing optically active dioxycyclohexane compound and optically active hydroxyethylenedioxycyclohexane compound

 The present invention relates to an optically active dioxycyclohexane compound, and the use of the compound.

The present invention relates to a method for producing an optically active hydroxyethylenedioxycyclohexane compound which is an important intermediate in the synthesis of 19-nor-monoactive vitamin D derivatives. Background art

Conventionally, activated vitamin D ₃ (1, 2 5- dihydroxy cholecalciferol sheet Hue port one Le) is calcium transport capacity in the small intestine, strong physiological activity such as bone mineral mobilization ability, important physiological functions of the human for its It is known to play a role.

 In addition, it has been reported that the 19-nor-form has a selective bioactive effect of inhibiting the growth of tumor cells without increasing the blood calcium ion concentration. Clinical development for developmental hyperparathyroidism (Te trahedron Let ters, 31, 1823 (1990), Tetrahedron Let ters, 32, 7663 (199 1), Tetrahedron Let ters, 33, 2937 (1992), etc.) .

 An optically active hydroxyethylenedioxycyclohexane compound represented by the general formula (3), for example, the following compound 丄 (X = Y = t_butyldimethylsilyl group) is a 19-nor-monoactive vitamin D derivative It is well known as one of the most important intermediates in production, the A-ring partial precursor.

(In the formula, T BS represents a t-butyldimethylsilyl group.)

Before the A-ring part, the method for producing the carcass so far has been as follows, for example, as shown in Scheme 1, (1) a homoallylic acid with an alkyl ester of propiolic acid. One-step production from one ter (Tetrahedron Letters, 39, 3359 (1998), Tetrahedron Letters, 39, 3363 (1998)), ② Two-step production from diepoxypentane and propargyl ether (Tetrahedron Letters, 37, 7637

(1996)).

 Scheme 1

(In the formula, Bn represents a benzyl group, TBS represents a t-butyldimethylsilyl group, MPM represents a p-methoxyphenylmethyl group, and TBDPS represents a t-butyldiphenylsilyl group.)

 However, any of the production methods described in the above scheme 1 has problems such as a long number of steps from the starting material and a low total yield of all the steps, and thus a more practical production method. The development of is desired.

 At present, research is being actively conducted to establish an efficient method for producing the A-ring partial precursor. Disclosure of the invention

 The present invention has been made in view of the above circumstances, and provides a key intermediate that can be efficiently converted to an A-ring partial precursor, which is an important intermediate when producing a 19-nor-monoactive vitamin D derivative. An object of the present invention is to provide an optically active dioxycyclohexane compound and a method for efficiently producing an optically active hydroxyethylenedioxycyclohexane compound which is an A-ring partial precursor using the compound.

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, the optically active dioxycyclohexane compounds represented by the general formulas (1) and (2) 9 In addition to finding that it can be an important key intermediate for the A-ring partial precursor in the production of 1-nor monoactive vitamin D derivatives, hydroxymethylation of this compound leads to the optically active hydroxyethylenediamine, the A-ring partial precursor. The present inventors have found that an oxycyclohexane compound can be efficiently produced, and have completed the present invention.

 That is, the present invention

 [1] The following general formula (1)

(1)

_xhi ,,, V, _0γ

(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Υ represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.)

An optically active dioxycyclohexane compound or an enantiomer thereof, which is represented by

 [2] The optically active dioxycyclohexane compound or an enantiomer thereof according to [1], wherein R is a halogen atom.

 [3] The following general formula (2)

(2)

 XO v, OY

(In the formula, R 'and R〃 independently represent a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y represent a hydrogen atom, a hydroxyl-protecting group or Represents a solid phase having a protecting group at the terminal.)

An optically active dioxycyclohexane compound or an enantiomer thereof, which is represented by

[4] The optically active dioxycyclohexane compound of [3], wherein R ′ and R〃 are halogen atoms, or an enantiomer thereof, [5] The following general formula (1)

(1

Χ0,... ^Ν , 0Υ

(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group. X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.)

A hydroxymethylation reaction is performed on an optically active dioxycyclohexane compound represented by the following general formula (3)

 Guang OH

(In the formula, X and Υ represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.)

A method for producing an optically active hydroxyethylenedioxycyclohexane compound, comprising obtaining a compound represented by

 [6] The method for producing an optically active hydroxyethylenedioxycyclohexane compound of [5], wherein R is a halogen atom.

I will provide a. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail.

 In the present specification, "η" is normal, "i" is iso, "s" is secondary, "t" is Yuri, "c" is cyclo, and "o" is cyclo. Orto means "m" means meta and "p" means para.

In the general formula (1), the substituent R represents a halogen atom, a substituted silyl group, a substituted hydrogen group or a substituted tin group. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 Examples of the substituted silyl group include a trisubstituted silyl group substituted by three groups selected from an alkyl group and a phenyl group (the phenyl group may be substituted with an alkoxy group). Specifically, trimethylsilyl, triethylsilyl, triisopropylsilyl, acetylethylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, texyldimethylsilyl, diphenylmethylsilyl, t-butyldiphenylsilyl, t-butyl Examples thereof include dimethoxyphenylsilyl and triphenylsilyl.

 Examples of the substituted boron group include a dialkylboron group (for example, dimethylboron, methylboron, di-n-butylboron, etc.), a diarylboron group (for example, diphenylboron, etc.), dialkoxy And a boron group (for example, diisopropoxyboron, ethylenedioxyboron, tetramethylethylenedioxyboron, etc.).

 Examples of the substituted tin group include a trialkyltin group (for example, trimethyltin, triethyltin, tri_n-propyltin, tri-n-butyltin, tri-c-hexyltin, etc.), a triaryltin group (for example, , Trifenyltin, etc.).

 Among these, as the substituent R, a halogen atom, trimethylsilyl, tetramethylethylenedioxyboron, or tri-n-butyltin is preferably used, more preferably a halogen atom, particularly a bromine atom.

 In the general formula (2), the substituents R ′ and R〃 independently represent a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group, wherein a halogen atom, a substituted silyl group, As the group, the substituted boron group, and the substituted tin group, those similar to the above can be used.

Examples of the substituted alkyl group include a linear, branched or cyclic C 1-6 alkyl group (the alkyl group may be optionally substituted with a halogen atom). For example, methyl, ethyl, n —Propyl, i-propyl, c-propyl, n-butyl , I-butyl, s-butyl, t-butyl, c-butyl, 1-methyl_c-propyl, 2-methyl-c-propyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl_n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n-propyl, c-pentyl, 1 -Methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c_propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-butyl Pill, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n- Butyl, 1,3-dimethyl-n- Tyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl_n-butyl, 2-ethyl-n-butyl, 1, 1 , 2-trimethyl-n-propyl, 1,2,2-trimethyl_n-propyl, 1-ethyl-1 1-methyl-n-propyl, 1-ethyl-2-methyl-n-propyl, c-hexyl, 1 -Methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1,2-dimethyl-c-butyl , 1,3-Dimethyl-c-butyl, 2,2-Dimethyl-c-butyl, 2,3-Dimethyl-c-butyl, 2,4-Dimethyl-c-butyl, 3,3-Dimethyl-c-butyl, 1n- Propyl-c-propyl, 2-n-propyl_c-propyl, 1- i-Propyl-c-propyl, 2-i-propyl_c-propyl, 1,2,2-trimethyl-c-propyl Mouth pill, 1,2,3-trimethyl-c-propyl, 2,2,3_trimethyl —C —propyl, 1-ethyl-2-methyl—c-propyl, 2-ethyl-1-methyl—c-propyl, 2-ethyl-2-methyl_c—propyl, 2-ethyl-3-methyl, C-propyl, etc. Is mentioned.

As the substituents R ′ and R〃, it is preferable to use both a halogen atom, one of which is methyl and the other is a halogen atom, one of which is ethyl, the other is a halogen atom, one is n-butyl and the other is a halogen atom, More preferably, both have a halogen atom, and particularly, both have a bromine atom. In the general formulas (1) and (2), the substituents X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.

 Examples of the hydroxyl-protecting group include, for example, Cl to 7-acyl groups (for example, formyl, acetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, propionyl, vivalyl, tigloyl) An arylcarbonyl group (for example, benzoyl, benzoylformyl, benzoylpropionyl, phenylpropionyl and the like), a C1-4 alkoxyl group (for example, methoxycarbonyl, Ethoxycarbonyl, n_propoxyl-proponyl, i-propoxyl-lponyl, n-butoxycarbonyl, i-butoxyl-carponyl, t-butoxyl-carponyl, t-amyloxycarbonyl, vinyloxyl-loxyl-ponyl, aryloxyl-loxyl Jp 2-( bird Methylsilyl) ethoxycarponyl, 2,2,2-trichloroethoxycarponyl, etc.), aryloxycarbonyl group (for example, benzyloxylponyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.). ), A C1-4 alkylaminocarboyl group (for example, methylcarbamoyl, ethylcarbamoyl, n-propylcaprolumyl and the like), an arylaminocarboxyl group (for example, phenylcarbamoyl and the like) ), Trialkylsilyl groups (for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, getylisopropylsilyl, dimethylisopropylsilyl, di-t-butylmethylsilyl, isopropyldimethylsilyl, tert-butylsilyl) Dimethylsilyl, texyldimethylsilyl, etc.), trialkylarylsilyl group (for example, diphenylmethylsilyl, t-butyldiphenylsilyl, t-butyldimethoxyphenylsilyl, triphenylsilyl, etc.) And the like.

 Examples of the solid phase having a hydroxyl-protecting group at the terminal include a liponyl group resin terminal, a liponyloxy group resin terminal, a liponylamino group resin terminal, and a silyl group resin terminal.

Examples of the resin used include polystyrene resin, PEG-polystyrene resin, PGA resin and the like. Among these, it is preferable to use, as the substituents X and Y, a Cl to 7 acyl group, a Cl to 4 alkoxycarbonyl group, a trialkylsilyl group, a trialkylarylsilyl group, a silyl group resin terminal, and the like. Preferred are a trialkylsilyl group, a trialkylarylsilyl group, and a silyl group resin terminal.

 The substituents X and Y may be the same or different from each other.

 Next, a method for producing the optically active dioxycyclohexane compound represented by the general formula (1) will be described.

 This compound is a novel compound that has not been known before, for example, the compound (R

= Bromine atom, X = Y = t-butyldimethylsilyl group) can be produced by the method shown in Scheme 2 below.

Scheme 2

(In the formula, T BS represents a t-butyldimethylsilyl group.)

 That is, the optically active cyclohexenone compound, which is the starting material, is epoxidized to form a cyclohexenoxide compound A, and then a bromethylene conversion reaction is performed on the ketone to form a bromomethylenecyclohexenoxide compound, and finally the epoxide is reduced. It can be produced by silylating the resulting hydroxyl group.

The oxidizing agent for the first epoxidation reaction is not particularly limited, and includes, for example, peracids such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide, oxygen and the like. Preferably, it is hydrogen peroxide. The amount of the oxidizing agent to be used is usually in the range of 0.8 to 50 times by mole, and particularly preferably in the range of 1.0 to 20 times by mole, relative to the substrate.

 The reaction solvent is not particularly limited as long as it is stable under the reaction conditions, and is inert and does not hinder the reaction. For example, the following solvents can be used.

 Specifically, water, alcohols (eg, methanol, ethanol, propanol, butanol, octanol, etc.), cellosolves (eg, methoxyethanol, ethoxyethanol, etc.), aprotic polar organic solvents (eg, For example, dimethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylperyl, sulfolane, N-methylpyrrolidone, N, N_dimethylimidazolidinone, etc., ethers (eg, getyl ether, diisopropyl ether, t Butyl methyl ether, tetrahydrofuran, dioxane, etc.), aliphatic hydrocarbons (for example, pentane, hexane, c-hexane, octane, decane, decalin, petroleum ether, etc.), aromatic hydrocarbons (benzene, Black mouth benzene, o-Dichloro mouth benzene, nitrobenzene, toluene, xylene, mesitylene, tetralin, etc., halogenated hydrocarbons (for example, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, etc.), ketones (acetone, methyl chloride) Tyl ketone, methyl butyl ketone, methyl isobutyl ketone, etc.), lower aliphatic acid esters (eg, methyl acetate, ethyl acetate, butyl acetate, methyl propionate, etc.), alkoxyalkanes (eg, dimethoxyethane, diethoxetane, etc.), Solvents such as nitriles (for example, acetonitrile, propionitrile, ptyronitrile, etc.). These solvents are appropriately selected according to the easiness of the reaction, and can be used alone or in combination of two or more. If necessary, water may be removed with a suitable dehydrating agent or desiccant to use as a non-aqueous solvent.

 The reaction temperature can usually be from 100 ° C. to the boiling point of the solvent used, but is preferably in the range of 150 ° C. to 50 ° C.

 The reaction time is usually 0.1 to 1000 hours.

After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product. In addition, using standard methods such as silica gel column chromatography By performing the purification, pure cyclohexenonoxide A can be isolated.

 Next, as a reaction for introducing bromethylene into a ketone, for example, a Wittig reaction using bromomethyl triphenylphosphonium bromide, or a Homon-Emmons reaction using, for example, diisopropyl bromomethyl phosphonate Preferred is a Wittig reaction using bromomethyltriphenylphosphonium bromide.

 In this case, the amount of bromomethyltriphenylphosphonium bromide to be used is usually in the range of 0.8 to 20 mol times, especially 1.0 to 5.0 mol times, relative to the substrate. preferable.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than ketone solvents can be used.

 The reaction temperature can be generally from —100 ° C. to the boiling point of the solvent to be used, but is preferably in the range of —50 to 50 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product. Furthermore, pure bromethylenecyclohexenoxide A can be isolated by performing purification by a conventional method such as silica gel column chromatography. The compound is obtained by reduction and silylation of the hydroxyl group.

 The reducing agent for the epoxide is not particularly limited, and examples thereof include diisobutylaluminum hydride, sodium borohydride, aluminum hydride, bismethoxyethoxyaluminum hydride, and the like. Or diisobutylaluminum hydride.

 The amount of the reducing agent to be used is generally in the range of 0.5 to 20 times by mole, particularly preferably in the range of 1.0 to 10 times by mole, relative to the substrate.

The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, ketones and esters can be used. The reaction temperature can usually be from −100 to the boiling point of the solvent used, but is preferably in the range of 180 to 50 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product. Furthermore, a pure hydroxyl compound can be isolated by performing purification by a conventional method such as silica gel column chromatography.

 The protective agent for protecting the hydroxyl group of the hydroxyl compound obtained as described above is not particularly limited, and examples thereof include an acylating agent, an oxypropylating agent, an aminocarbonylating agent, and a silylating agent. And the like, and preferably a silylating agent.

 Such a silylating agent is not particularly limited, and includes, for example, trimethylsilyl chloride, t-butyldimethylsilyl chloride, diphenylt-butylsilyl chloride and the like.

 The amount of the silylating agent to be used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times with respect to the substrate.

 In this case, to promote the reaction, a base may be allowed to coexist in the reaction system. Examples of such a base include getylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, DBU, and N-methylmorpholine. Amines such as N, N-N-dimethylaniline, pyridines such as pyridine, methylethylpyridine, lutidine, pyridines such as 4-N, N-dimethylaminopyridine, imidazole and pyrazole, and preferably imidazole. It is one le.

 The amount of the base to be used is generally in the range of 0.5 to 20 mol times, preferably in the range of 1.0 to 10 mol times, based on the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water and alcohols can be used.

 The reaction temperature can usually be from 100 ° C. to the boiling point of the solvent used, but is preferably in the range of 150 ° C. to 50 ° C.

The reaction time is usually 0.1 to 1000 hours. After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product. Furthermore, a pure compound can be isolated by performing purification by a conventional method such as silica gel column chromatography. After reducing the oxide, the resulting hydroxyl group is reacted with a resin having a reactive silyl group at the terminal to obtain a compound A (R = bromine atom, X or

One of Y = t_butyldimethylsilyl group and the other = silyl group resin end) can be produced.

 Since Compound A is supported on a solid phase, it can be easily separated from the reaction system.

It is suitable for high-speed synthesis by a combinatorial real chemistry automatic synthesizer.

(In the formula, T BS represents a t-butyldimethylsilyl group.

 Et represents an ethyl group. ③ represents a solid support. In addition, as the compound represented by the above general formula (1), for example, a compound 丄 (= tetramethylethylenedioxyboron, X = Y = t-butyldimethylsilyl group) is produced by the method shown in the following scheme 3. can do.

Love

(In the formula, T BS represents a t-butyldimethylsilyl group.)

That is, the compound can be produced by using the compound obtained above as a raw material, lithifying the compound, and then treating the compound with a borating agent. Examples of the lithiation agent include n-butyllithium, s-butyllithium, t-butyllithium and the like.

 The amount of the lithiating agent to be used is usually in the range of 0.5 to 20 mole times, particularly preferably in the range of 1.0 to 10 mole times with respect to the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, alcohols, ketones, and esters can be used.

 The reaction temperature can be generally from 100 ° C. to the boiling point of the solvent used, but is preferably from 180 ° C. to 0 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 The lithiated compound is not isolated, but a boron compound is directly added to the reaction system to obtain a boron compound. Further, the compound I can be synthesized by treating the obtained boron compound with pinacol.

 Here, the boronating agent is not particularly limited, and includes, for example, trimethoxypolan, triethoxypolan, triisopropoxypolan and the like. The amount of the boronating agent used is usually in the range of 0.5 to 20 mole times, particularly preferably in the range of 1.0 to 10 mole times with respect to the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.

 The reaction temperature can be usually from —100 ° C. to the boiling point of the solvent to be used, but is preferably in the range of —80 to 50 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

 Furthermore, pure compound 丄 can be isolated by performing purification by a conventional method such as silica gel column chromatography.

Further, as the compound represented by the general formula (1), for example, a compound rimethylsilyl, X = Y = t-butyldimethylsilyl group) can be produced by the method shown in the following scheme 4. Scheme 4

TBSO、、、 、OTBS SiMec

TBSO,,, OTBS

 5 8

(In the formula, TBS represents a t-butyldimethylsilyl group, and Me represents a methyl group.) That is, the compound obtained above is used as a raw material, lithiated, and then treated with a silylating agent. Can be.

 Examples of the lithiating agent include the same reagents as described above.

 The amount of the lithiating agent used is usually in the range of 0.5 to 20 moles per mole of the substrate.

In particular, a range of 1.0 to 10 mole times is preferable.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, alcohols, ketones, and esters can be used.

 The reaction temperature can usually be from −100 ° C. to the boiling point of the solvent used, but is preferably in the range of −80 to 0 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 The lithiated compound is not isolated but is silylated by adding a silylating agent to the reaction system.

 The silylating agent is not particularly restricted but includes, for example, chlorotrimethylsilane, chlorotri-n-butylsilane, bromotri-n-butylethylsilane, chlorotri-n-octylsilane, bromotri-n-octylsilane, chlorotriphenylsilane, bromotriphenylsilane, etc. Is mentioned.

 The amount of the silylating agent to be used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 10 mol times with respect to the substrate.

The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is. The reaction temperature can be usually from 110 ° C. to the boiling point of the solvent used, but is preferably in the range of −80 to 50.

 The reaction time is usually 0.1 to 1000 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

 Further, pure compound A can be isolated by performing purification by a conventional method such as silica gel column chromatography.

 The optically active cyclohexenone compound used as a starting material for producing the optically active dioxycyclohexane compound represented by the general formula (1) is, as shown in Scheme 5, Tetrahedron Letters, 38, 8299 (1997) , J. Am. Chem. Soc., 121,

3640 (1999).

 Scheme 5

(In the formula, T BS represents a t-butyldimethylsilyl group.)

 That is, the optically active chlorohydrin ester is iodinated to give an eodohydrin form 10, and then the hydroxyl group is silylated to give a siloxy form 11, and further reacted with a vinyl Grignard reagent to form a homoallyl ether form 12. And finally by cyclization with Ti.

 Next, a method for producing the optically active dioxycyclohexane compound represented by the general formula (2) will be described.

This compound is also a novel compound that has not been known so far. For example, compound 14 (R ′ = R ″ = bromine atom, X = Y = t-butyldimethylsilyl group) is prepared by the method shown in Scheme 6 below. Can be manufactured. Scheme 6

 3 13

 14

(In the formula, T BS represents a t-butyldimethylsilyl group.)

 That is, the optically active cyclohexenone compound, which is the starting material, is epoxidized to give a cyclohexenonoxide A, and then the ketone is subjected to dibromomethylene conversion reaction to give a dibromomethylenecyclohexenoxide 13. It can be produced by reducing epoxides and silylating hydroxyl groups.

 As the oxidizing agent for the first epoxidation reaction, the same oxidizing agent as the compound represented by the general formula (1) can be used.

 The amount of the oxidizing agent to be used is usually in the range of 0.850 times by mole, particularly preferably in the range of 1.020 times by mole relative to the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the above-mentioned solvents can be used.

 The reaction temperature can be generally from 100 ° C. to the boiling point of the solvent used, but is preferably in the range of 150 ° C.

 The reaction time is usually 0.1100 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

Further, pure cyclohexenonoxide A can be isolated by purification by a conventional method such as silica gel column chromatography. Next, the reaction for introducing dibromomethylene into a ketone is not particularly limited, and examples thereof include a Wittig reaction using carbon tetrachloride and triphenylphosphine.

 The amount of carbon tetrachloride to be used is usually in the range of 0.8 to 20 times by mole, particularly preferably in the range of 1.0 to 5.0 times by mole, relative to the substrate.

 The amount of triphenylphosphine used is usually in the range of 0.8 to 20 mole times, particularly preferably in the range of 1.0 to 5.0 mole times, relative to the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than ketones can be used.

 The reaction temperature can be usually from 110 Ot to the boiling point of the solvent used, but is preferably in the range of -50 to 50 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

 Furthermore, pure dibromomethylenecyclohexenoxide 13 can be isolated by purification by a conventional method such as silica gel column chromatography. Compound 14 is obtained by reducing the compound and silylating the hydroxyl group.

 Here, examples of the epoxide reducing agent include the same ones as described above, and it is particularly preferable to use diisobutylaluminum hydride.

 The amount of the reducing agent to be used is generally in the range of 0.5 to 20 mol times, preferably in the range of 1.0 to 10 mol times, relative to the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, ketones and esters can be used. The reaction temperature can be generally from 10 ° C. to the boiling point of the solvent used, but is preferably in the range of −80 ° C. to 50 ° C.

The reaction time is usually 0.1 to 1000 hours. After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

 Furthermore, a pure hydroxyl form can be isolated by performing purification by a conventional method such as silica gel gel chromatography.

 Examples of the protecting agent for protecting the hydroxyl group include the same as described above, but it is preferable to use a silylating agent.

 Here, the type and amount of the silylating agent, the type and amount of the base used as the reaction accelerator, and the reaction conditions are the same as described above.

 After completion of the silylation reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

 Furthermore, pure compound 14 can be isolated by performing purification by a conventional method such as silica gel column chromatography.

 Next, a method for producing the optically active hydroxyethylenedioxycyclohexane compound represented by the general formula (3) will be described.

 The compound can be produced by subjecting the optically active dioxycyclohexane compound represented by the general formula (1) obtained above to a hydroxymethylation reaction.

 For example, compound 丄 (X = Y = t-butyldimethylsilyl group) can be produced by lithiation of the above compound and then reacting with formaldehyde. Examples of lithiation agents include n-butyllithium and s Monobutyl lithium, t-butyl lithium and the like.

 The amount of the lithiating agent to be used is usually in the range of 0.5 to 20 mol times, particularly preferably in the range of 1.0 to 0 mol times, relative to the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and among the above-mentioned solvents, solvents other than water, alcohols, ketones, and esters can be used.

The reaction temperature can be generally from —100 to the boiling point of the solvent to be used, but is preferably in the range of 180 to 0 ° C. The reaction time is usually 0.1 to 1000 hours.

 The lithiated compound is not isolated, and formaldehyde is added to the reaction system as it is, followed by hydroxymethyl irrigation.

 The amount of formaldehyde to be used is usually in the range of 0.5 to 20 moles, preferably 1.0 to 10 moles per mole of the substrate.

 The reaction solvent is not particularly limited as long as it does not participate in the reaction, and the solvent used for lithiation can be used as it is.

 The reaction temperature can usually be from -10 to the boiling point of the solvent used, but is preferably in the range of 180 to 50 ° C.

 The reaction time is usually 0.1 to 1000 hours.

 After completion of the reaction, the desired product is extracted with an appropriate solvent, and the solvent is concentrated under reduced pressure to obtain a crude product.

 Furthermore, purification can be performed by a conventional method such as silica gel column chromatography.

 Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.

Example 1 Synthesis of Xenon Oxide Form

(Wherein, TBS represents a t-butyldimethylsilyl group.)

In a mixture of ice-cooled optically active 5-siloxy-2-cyclohexenone (226mg, 1.Ommol) and 35% hydrogen peroxide solution (0.8mL, 1Ommo1), methanol (38mL) and 3mol An aqueous solution of ZL sodium hydroxide (33 mL, 0.1 lmmol) was added. After the mixed solution was stirred under ice cooling for 6 hours, a saturated aqueous solution of ammonium chloride (3 mL) was added. Then, the mixture was extracted three times with ether (5 mL), and the organic layer was dried over anhydrous magnesium sulfate.

 After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain optically active 5-siloxy-2,3-epoxycyclohexanone in a yield of 83% (204 mg). I got it.

 Ή The stereoisomer ratio was> 95: <5 from NMR and GC analysis.

_{Ή NMR (300 MHz, CDC1 3} ) (54. 2-4.33 (m, 1H, CHOSi), 3.54-3.59 (m, 1 H, CH 2 CHO), 3.26 (d, J = 3.9Hz, 1H, CH) CHO), 2.77 (dd, J = 3.0, 15.3Hz, 1H, one of CH ₂ CH)), 2.39 (dd, J = 4.2, 15.3Hz, 1H, one of CH ₂ ), 2.19 (dd, J = 4.2 , 15.3Hz, 1H, one of CH ₂ C (= 0)), 2.00 (dt, J = 15.3, 3.3Hz, 1H, one of CH ₂ ), 0.85 (s, 9H, t-Bu), 0.04 and 0.03 _{(2s, 6H, 2SiCH 3)} .

^{13 C NMR (75 MHz, CDC1} 3) 6204.8, 67.3, 55.4, 54.7,44.9, 32.9, 25.5, 1 7.8, -5.0, -5.1.

IR (neat) 2929, 2888, 2857, 1726, 1472, 1406, 1361, 1331, 1255, 1075, 10 31, 985, 935, 871, 837, 778, 715 cm " ¹ .

[Example 2]

Of,

(Wherein, TBS represents a t-butyldimethylsilyl group.)

 To a suspension of bromomethyltriphenylphosphonium bromide (567 mg, 1.3 mmo 1) in toluene (2 mL) was added potassium pistrimethylsilylamide (0.5 M / toluene solution, 2.6 mL, 1. Then, the mixture was stirred at room temperature for 30 minutes.

After cooling this mixed solution to 0 ° C, a toluene solution of 5-siloxy 2,3-epoxycyclohexanone 3 (242 mg, 1.0 mmo 1) was added, and the reaction solution was added. Was raised to room temperature over 30 minutes.

 The reaction solution was concentrated under reduced pressure, and ethyl ether (2 mL) and hexane (40 mL) were added to the obtained residue, and the precipitated crystals were filtered through celite.

 The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography 1 to give 1-bromomethylene-15-siloxy-1,2,3-epoxycyclohexane _ in a yield of 82% (262 mg). I got it.

_{Ή NMR (300 MHz, CDC1 3} ) 50.06 (s, 6H), 0.86 (s, 9H), 1.81 (ddd, J = 2 .4, 6.9, 15.0 Hz, 1H), 2.16 (ddd, J = 2.1, 8.4 , 15.9 Hz, 1H), 2.27 (dd, J = 3.9, 15.0 Hz, 1H), 2.42 (br d, J = 15.9 Hz, 1H), 3.38-3.45 (m, 1H), 3.49 (d, 4.2 Hz, 1H), 3.87- 4.02 (m, 1H), 6.48 (br s, 1H).

^{13 C NMR (75 MHz, CDC1} 3) δ-4.7, -4.6, 18.1, 25.8, 33.9, 35.4, 54.1, 54 .7, 64.3, 109.2, 137.5.

IR (neat) 2928, 2856, 1621, 1471, 1360, 1254, 1092, 876, 836, 777 cm one ¹

Example 3 Synthesis of Optically Active Dioxycycline Hexane Compound 5

(In the formula, TBS represents a t-butyldimethylsilyl group.)

 Under ice-cooling, a solution of 1-bromomethylene-5-siloxy-2,3-epoxycyclohexa y (100 mg, 0.313 mmo 1) in THF (3 mL) was added with diisobutylaluminum hydride (1.0 M / Hexane solution, 0.94 mL, 0.94 mmo 1) was added, and the mixture was stirred as it was at 0 ° C for 15 hours.

Water (0.18 mL), sodium fluoride (1 g), and celite (1 g) were added to the reaction solution, and the mixture was filtered through celite. The crude product of 1-bromomethylene-13-hydroxy-5-cyclooxycyclohexane obtained by concentrating the filtrate under reduced pressure was directly used in the next reaction.

_{Ή NMR (300 MHz, CDC1 3} ) (50.07 and 0.09 (2s, 6H), 0.88 (s, 9H), 1.42 (d, J = 5.1Hz, 1H, OH), 1.74 (ddd, J = 3.6, 7.2, 13.2 Hz, 1H), 1.83 (ddd, J = 3.9, 6.9, 13.2 Hz, 1H), 2.15 (dd, J-7.5, 13.5 Hz, 1H), 2.43-2.54 (m, 2H), 4.04-4.16 (m , 2H), 6.02 (brs).

^{13 C NMR (75 MHz, CDC1} 3) 5 - 4.9, -4.7, 18.1, 25.8, 39.2, 42.5, 43.1, 66 .9 (two carbons), 101.9, 138.8.

 The crude product of 1-bromomethylene-13-hydroxy-5-siloxycyclohexane obtained above and imidazole (43 mg, 0.63 mmol) in dimethylformamide (lmL) Then, t-butyldimethylsilyl chloride (7 lmg, 0.47 mmo 1) was added thereto, followed by stirring at room temperature for 12 hours.

 After adding saturated aqueous sodium hydrogen carbonate (3 mL), the mixture was extracted three times with hexane (4 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography, and 1-bromomethylene-3,5-disiloxycyclohexane was obtained. Hexane was obtained in a yield of 68% (93 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δ 0.04 (s, 6H), 0.06 and 0.09 (2s, each 3H), 0 .87 and 0.89 (2s, each 9H), 1.62-1.84 (m, 2H), 2.09 ( ddd, J = 0.9, 7.5, 13.5 Hz, 1H), 2.30-2.48 (m, 3H), 4.02-4.15 (m, 2H), 5.94 (br s, 1H). 1 3 C NMR (75 MHz, CDC1 3 ) δ-4.86, -4.74, -4.67, -4.64, 18.16, 18.20, 25.87, 25.90, 39.2, 43.2, 43.6, 67.1, 67.4, 101.2, 139.3.

IR (neat) 2953, 2857, 1637, 1471, 1361, 1255, 1099, 1025, 914, 836, 775 cm- ¹ .

[Example 4] Synthesis of optically active dioxycyclohexane compound 7

(式中、 TBSは t _プチルジメチルシリル基を表す。 ）

(In the formula, TBS represents a t_butyldimethylsilyl group.)

 To a solution of 1-bromomethylene-3,5-disiloxycyclohexane (348 mg, 0.8 Ommo 1) in getyl ether (3 mL), add t-butyllithium (1.35 M / pentane solution, 1.30 mL, 1 76mmo 1) was added at -78, and the mixture was stirred as it was at -78 ° C for 1 hour.

 Triisopropoxypolane (2.0 MZ Jetyl ether solution, 0.6 mL, 1.2 mmo 1) was added at —78 ° C, and the reaction solution was warmed to room temperature over 4 hours, and then saturated An aqueous ammonia solution (8 mL) and ethyl acetate (8 mL) were added. Subsequently, the mixture was extracted twice with ethyl acetate (6 mL), and the organic layer was concentrated under reduced pressure.

 Ethyl acetate (3 mL) was added to the residue for dissolution, and to this was added pinacol (113 mg, 0.96 mmol 1) and magnesium sulfate (1.0 g), and the mixture was stirred at room temperature for 12 hours. did.

 After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give the compound in a yield of 93% (415 mg).

_{Ή NMR (300 MHz, CDC1 3} ) δ 5.12 (s, 1H), 4.03-4.11 (m, 2H), 2.67 (dd, J = 3.6, 13.2 Hz, 1H), 2.54 (dd, J = 6.9,13.2, Hz, 1H), 2.36 (dd, J = 3.6, 12.9 Hz, 1H), 2.13 (dd, J = 7.5, 12.9 Hz, 1H), 1.62-1.76 (m, 2H), 1.22 (s, 6H), 1.21 (s, 6H), 0.86 (s, 9H), 0.84 (s, 9H), 0.043, 0.036, 0.008 and 0.004 (4s, each 3H).

^{1 3 C NMR (75 MHz,} CDC1 3) (5160.1, 115.6 (br s), 82.5, 68.3, 67.9, 48.0, 43.1, 0.8, 25.8, 25.7, 24.9, 24.6, 18.1, 17.9, -4.9, -5.0, -5.1, -5.2.IR (neat) 2954, 2856, 1645, 1471, 1386, 1256, 1096, 1028, 837, 775 cm

Example 5 Synthesis of Optically Active Diosane Compound

(式中、 TBSは t一プチルジメチルシリル基、 Meはメチル基を表す。 ） 1一ブロムメチレン一 3， 5 _ジシロキシシクロへキサン (174mg, 0 . 40 mm o 1 ) のジェチルェ一テル (2mL) 溶液に、 t一ブチルリチウム ( 1. 35MZペンタン液， 0. 65mL, 0. 88mmo 1 ) を一 78 で加え 、 そのまま一 78 X：で 1時間撹拌した。

(Wherein TBS represents t-butyldimethylsilyl group and Me represents a methyl group.) Jethyl ether of 1-bromomethylene-1, 3,5-disiloxycyclohexane (174 mg, 0.40 mmo 1) ( 2mL) To the solution was added t-butyllithium (1.35MZ pentane solution, 0.65mL, 0.88mmo1) at 178, and the mixture was stirred as it was at 178X: for 1 hour.

 Next, chlorotrimethylsilane (76 L, 0.6 mmo 1) was added at −78 ° C., the reaction solution was heated to room temperature over 3 hours, and a saturated aqueous solution of ammonium chloride (4 mL) was added.

 Subsequently, the mixture was extracted twice with getyl ether (3 mL), and the organic layer was dried (magnesium sulfate).

 After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the compound in a yield of 89% (153 mg).

_{Ή NMR (300 MHz, CDC1 3} ) 55.22 (s, 1H), 4.01-4.13 (m, 2H), 2.49 (dd, J = 3.6, 12.9 Hz, 1H), 2.32 (dd, J = 3.0, 13.2 Hz, 1H), 2.08-2.17 (m, 2H), 1.73—1.83 (m, 1H), 1.56-1.67 (m, 1H), 0.89 and 0.86 (2s, each 9H), 0.097 (s, 9H), 0.06 and 0.03 (2s, each 6H).

^{13 C NMR (75 MHz, CDC1} 3) 5152.3, 126.0, 68.1, 67.6, 47.9, 43,1, 42.8, 26.0, 25.8, 18.3, 0.5, -4.5, -4.59, -4.62, -4.7.

IR (neat) 2952, 2857, 1624, 1472, 1362, 1250, 1098, 1028, 836, 774, 691 cm " ¹ .

[Example 6] Synthesis of 'oxide 13

(In the formula, TBS represents a t-butyldimethylsilyl group.) To a solution of carbon tetrabromide (830 mg, 2.5 mmo 1) in dichloromethane (3 mL) was added triphenylphosphine (1.31 g 5. Ommol) at 0 ° C, and the mixture was stirred at 0 ° C for 5 minutes. did.

 After adding 2-methyl-1-butene (1.4 mL 12.5 mmol 1) and stirring for 5 minutes, a solution of 5-siloxy-23-epoxycyclohexanone (242 mg 1.Ommol) in dichloromethane (3 mL) was added. C. and the reaction was stirred for 30 minutes.

 Thereafter, the reaction solution was diluted with hexane (30 mL) and filtered through celite.

 The crude product of 1-dibromomethylene-5-siloxy_23-epoxycyclohexane obtained by concentrating the filtrate under reduced pressure was used for the next reaction as it was.

_{Ή NMR (300 MHz, CDC1 3} ) δ 3.85-3.95 (m, 2H), 3. 0-3. 4 (m, 1H), 2.52 (dd, J = 3.6, 15.3Hz, 1H), 2.28 (dd, J = 4.5, 15.0 Hz, 1H), 2.11 (dd, J = 6.0, 15.3 Hz, 1H), 1.75 (ddd, J = 2.7,7.8, 15.0 Hz, 1H), 0.87 (s, 9H), 0.061 (s 3H), 0.05 (s, 3H).

^{1 3 C NMR (75 MHz,} CDC1 3) (5137.0, 93.6, 64.3, 54.6, 53.8, 39.2, 33.5, 2 5.8, 18.1 -4.66, -4.74.

Example 7 Synthesis of Optically Active Dioxycyclohexane Compound 14

(式中、 TBSは t一プチルジメチルシリル基を表す。 ）

(Wherein, TBS represents a t-butyldimethylsilyl group.)

Under ice-cooling, diisobutylaluminum hydride (0.96MZ) was added to a solution of the crude product of 1-dibromomethylene-15-siloxy-2,3-epoxycycline hexane obtained in Example 6 in hexane (5 mL). Hexane solution, 2.08 mL, 2.0 mm o 1) was added, and the mixture was stirred at 0 ° C for 1 hour. Water (0.36 mL) was carefully added to the reaction solution at 0 ° C., followed by stirring for 30 minutes. Sodium fluoride (lg) and celite (lg) were added, and the mixture was filtered through celite.

 The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 1-dibromomethylene-3-hydroxy-5-siloxycyclohexane in a yield of 74% (287 mg). Was.

[a] ₂₄ ^D = +10.68 (cl.47 CHC1 ₃ ).

_{Ή NMR (300 MHz, CDC1 3} ) 54.80-4.20 (m, 2H), 2.73 (dd, J = 3.9, 13.5 Hz, 1H), 2.42-2.56 (m, 2H), 2.38 (dd, J = 7.5, 3.5 Hz, 1H), 1.68-1.86 (m, 2H), 1.58 (s, 1H), 0.88 (s, 9H), 0.081 (s, 3H), 0.064 (s, 3H).

^{13 C NMR (75 MHz, CDC1} 3) (5139.3, 85.8, 66.8, 66.6, 42.4, 42.2, 41.9, 2 5.7, 17.9, -5.07, -5.14.

 IR (neat) 3350, 2928, 2856, 1470, 1254, 1103, 908, 837, 776 cm—

_{.. Anal Calc for C, 3} H 24 Br 2 0 2 Si:. C, 39.01; H, 6.04 Found: C, 38.91; H, 5.94.

 To a solution of 1-dibromomethylene-3-hydroxy-5-siloxycyclohexane (272 mg, 0.7 mmo 1) obtained above and imidazole (95 mg, 1.4 mmol) in dimethylformamide (2 mL) At 0 ° C., t-butyldimethylsilyl chloride (136 mg, 0.9 mmol) was added, and the mixture was stirred at room temperature for 12 hours.

 After adding water (2 mL), the mixture was extracted three times with getyl ether (6 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography, and purified by 1-dibromomethylene-3,5-disiloxycyclohexane. Hexane 14 was obtained in a yield of 96% (348 mg).

[a] ₃₀ ^D = +2.27 (cl.21 CHC1 ₃ ).

_{Ή NMR (300 MHz, CDC1 3} ) (54.06-4.14 (m, 2H), 2.56 (dd, J = 3.3, 13.5Hz,

2H), 2.37 (dd, J = 7.2, 13.8 Hz, 2H), 1.69 (t, J = 5.4 Hz, 2H), 0.892 (s

, 9H), 0.889 (s, 9H), 0.079 (s, 3H), 0.062 (s, 3H). ^{13 C NMR (75 MHz, CDC1} 3) (5139.9, 85.1, 67.0, 42.8, 42.5, 18.0, -5.08, -5.14.

IR (neat) 2928, 2856, 1471, 1362, 1256, 1092, 1027, 958, 838, 695 cm ¹ Anal.Calc. For C ₁₉ H ₃₈ Br ₂ 0 ₂ Si ₂ : C, 44.36; H, 7.44. Found : C, 44.40; H, 7.45.

[Example 8] Synthesis of optically active hydroxyethylenedioxycyclohexane compound 丄

(Wherein, TBS represents a t-butyldimethylsilyl group.)

 To a solution of 1-bromomethylene-1,3,5-disiloxycyclohexane (40.3 mg, 0. Immol) in getyl ether (lmL) at —78 ° C, t-butyllithium (1.7 M / pentane) The solution, 0.14 mL, 0.24 mmo 1) was added, and the temperature was raised to 120 ° C over 1 hour.

 To this was added an excessive amount of formaldehyde (detjyl ether solution), and the temperature was raised to room temperature.

 After adding a saturated aqueous solution of ammonium chloride, the mixture was extracted with getyl ether, and the organic layer was dried (anhydrous magnesium sulfate).

 After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to give 1- (2-hydroxyethylidene) -1,5-disiloxycyclohexane 丄 in a yield. Obtained in 52% (17.7 mg).

_{Ή NMR (300 MHz, CDC1 3} ) (55.60 (t, J = 7.2 Hz, vinylic), 3.95-4.20 (m, 4H, CH0 and CH 2 0), 2.25-2.40 (m, 2H), 2.18 (dd, J = 3.3, 13.2Hz, 1H, allylic), 2.05 (dd, J = 8.1, 13.2Hz, 1H, allylic), 1.75- 1.86 (ra, 1H), 1.69 (br s, 1H, OH), 1.63 (dd, J = 3.0, 9. OHz, 1H, C¾), 0.87 (s, 18H, t-Bu), 0.06 (s, 6H, SiCH ₃ ), 0.05 and 0.04 (2s, each 3H, SiCH ₃ ).

^{13 C NMR (75 MHz, CDC1} 3) d 138.2, 125.2, 68.1, 67.9, 58.4, 45.6, 43.4, 36.6, 25.9, 18.2, -4.57, -4.66, - 4 · 70, -4.74.

IR (neat) 3367, 2928, 2856, 1654, 1472, 1361, 1253, 1109, 1084, 1082,83 5,774 cm " ¹ .

Example 9 Synthesis of Optically Active Dioxycyclohexane Compound 15

(式中、 TBSは tーブチルジメチルシリル基を表す。 Buは、 n_ブチル基を 表す。 )

(In the formula, TBS represents a t-butyldimethylsilyl group. Bu represents an n_butyl group.)

 To a solution of 1-bromomethylene-1,3,5-disiloxycyclohexane (348 mg, 0 • 80 mmo 1) in getyl ether (3 mL), add t-butyllithium (1.35 M / pentane solution, 1.3 OmL, 1.76 mm o 1) was added at −78 ° C., and the mixture was stirred as it was at −78 ° C. for 1 hour.

 Subsequently, chlorotri-n-butyltin (0.434 mL, 1.2 mmo 1) was added at _78 ° C, and the reaction solution was heated to room temperature over 3 hours.

 After adding saturated aqueous sodium hydrogen carbonate (1 OmL), the reaction solution was extracted twice with hexane (1 OmL), and the organic layer was dried (magnesium sulfate).

 After filtering off magnesium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain Compound 15 in a yield of 93% (48 1 mg).

_{Ή NMR (CDC1 3) δ 5.47} (s, 1H), 3.99-4.13 (m, 2H), 2.33-2.40 (m, 2H), 2.22 (dd, J = 3.9, 13.5Hz, 1H), 2.11 (dd, J = 9.6, 12.9Hz, 1H), 1.82-1.90 (m, 1H), 1.43-1.61 (m, 7H), 1.24-1.38 (m, 6H), 0.78-1.06 (m, 6H), 0.89 (t, 9H), 0.90 (s, 18H), 0.067 and 0.062 (2s, each 3H), 0.030 (s, 6 H);

_{^{13 C NMR (CDC1 3) (}} 5 152.1, 124.1, 68.3, 67.7, 47.1, 46.5, 43.1, 29.3, 2 7.4, 26.0, 25.8, 18.2, 18.1, 13.8, 10.3, -4.5, -4.6, -4.8;

 IR (neat) 2926, 2862, 1613, 1463, 1376, 1361, 1255, 1099, 836, 775, 69

1;

(a 3 ²⁵ _D -14.3 (c 7.90, CHC1 ₃ ) ;.

Anal.Calcd. For C ₃₁ H ₆₆ 0 ₂ Si ₂ Sn: C, 57.66; H, 10.30. Found: C, 57.28; H, 10.32.

[Example l o] Synthesis of optically active dioxycyclohexane compound A

TBSO ,,,

(Wherein, TBS represents a t-butyldimethylsilyl group.

 Et represents an ethyl group. ③ indicates a solid support)

5 PS-DES resin (Argonaut, 0.6-1. OmmolZg, 1.00 g) is charged into a 5 mL OmL reaction tube (Aldrich), dried under reduced pressure for 30 minutes, and then argon. Purged.

 To this was added a solution of 1,3-dichloro-5,5-dimethylhydantoin (443 mg, 2.25 mm 01) in methylene chloride (1 ImL), and the mixture was slowly stirred at room temperature for 2 hours.

 The reaction solution was filtered under argon, and the obtained resin was washed three times with methylene chloride (2 OmL) and further three times with THF (2 OmL), and then dried under reduced pressure.

Subsequently, the 1-bromomethylene-3-hydroxy-5-siloxycyclohexane (723 mg, 2.25 mmo 1) obtained in Example 3 and imidazole (18 Omg, 2 63mmo 1) methylene chloride (25 mL) solution and slowly stirred at room temperature for 4 hours.

 The reaction solution was filtered, and the obtained resin was washed twice with ether (18 mL). After the filtrate was washed twice with water (20 mL), the organic layer was dried (magnesium sulfate), filtered through magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was treated by silica gel column chromatography. As a result, 1-bromomethylene-13-hydroxy-5-siloxycyclohexane (382 mg, 1.19 mmol) was recovered as a raw material.

 The resin was washed three times with THF-water (3/1 (v / v), 12 mL), twice with ethanol (12 mL), and twice with ether (18 mL), and dried under reduced pressure overnight. An optically active vinylidenecyclohexane compound 5 having a silyl group resin terminal was obtained in a yield of 90% (1.31 g) based on the recovered raw material.

Loading of the obtained resin was determined to be 0.738 mmolZg by decomposing the resin with monopyridine hydrofluorate and then analyzing the resulting alcohol form by ¹ HNMR.

 That is, a resin (144 mg) and THF (3 mL) were charged into a syringe type PP reactor (EYELA RT 5-S100, manufactured by Takeda Rika), and monohydropyridine hydrofluoride (0.1 mL) was added thereto. The mixture was stirred at room temperature for 6 hours.

 To the reaction solution, 1,4-dibromobenzene (25.6 mg) was added as an internal standard, and the mixture was filtered with THF (3 mL).

 Ethyl acetate (4 mL) was added to the filtrate, washed with saturated aqueous sodium hydrogen carbonate (3 mL), and further extracted twice from the aqueous layer with ethyl acetate (3 mL).

The combined organic layer was dried (magnesium sulfate), filtered through magnesium sulfate, and the filtrate was concentrated under reduced pressure, and the resulting residue was analyzed by ¹ H NMR.

 As a result, the bromomethylenecyclohexanediol was 0.1063 mmol, and the loading of the resin was calculated to be 0.738 mmolZg.

According to the present invention, 19 an-nor one active vitamin D derivatives and active vitamin D ₃ derivatives hexane compound to a key intermediate optically active hydroxyethylene di O key Shishikuro in manufacturing, hexanes optically active Jiokishishikuro By using a compound, it can be produced relatively easily and efficiently.

Claims

The scope of the claims  1. The following general formula (1)

(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group. X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.) Or an optically active dioxycyclohexane compound or an enantiomer thereof.  2. The optically active dioxycyclohexane compound or an enantiomer thereof according to claim 1, wherein R is a halogen atom. 3. The following general formula (2)

(In the formula, R ′ and R〃 independently represent a substituted alkyl group, a halogen atom, a substituted silyl group, a substituted boron group or a substituted tin group. X and Y represent a hydrogen atom, a hydroxyl-protecting group or Represents a solid phase having a protecting group at the terminal.) Or an optically active dioxycyclohexane compound or an enantiomer thereof.  4. The optically active dioxycyclohexane compound or an enantiomer thereof according to claim 3, wherein R ′ and R〃 are a halogen atom.  5. The following general formula (1) XO

(In the formula, R represents a halogen atom, a substituted silyl group, a substituted boron group, or a substituted tin group. X and Y represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.) A hydroxymethylation reaction is performed on an optically active dioxycyclohexane compound represented by the following general formula (3)

(In the formula, X and Υ represent a hydrogen atom, a protecting group for a hydroxyl group, or a solid phase having the protecting group at the terminal.) A method for producing an optically active hydroxyethylenedioxycyclohexane compound, characterized by obtaining a compound represented by the formula:  6. The method for producing an optically active hydroxyethylenedioxycyclohexane compound according to claim 5, wherein R is a halogen atom.